The immediate and long-term goals of the principal investigator are to become an independent clinical scientist with the ability to integrate and utilize biologically relevant findings from both clinical trials and correlative laboratory studies to develop innovative and effective therapies for multiple myeloma (MM). Therefore, the principal investigator proposes to undertake a career development plan that provides training in both clinical and laboratory research as well as the opportunity to implement these skills in a fully integrated research program. The application proposes an orderly series of research endeavors that will take advantage of the unique academic setting and provide invaluable experience in translational science as well as an organized educational program designed to formally train the principal investigator in clinical research. Furthermore, the expertise of the mentor and the highly conducive environment for developing and carrying out novel clinical anticancer strategies will facilitate the principal investigator's transition to independence. MM is characterized by the accumulation of malignant plasma cells that form the bulk of the tumor mass. However, these cells are relatively quiescent suggesting that the proliferative capacity of the tumor lies within a specialized subpopulation of cells, MM stem cells or progenitors that are responsible for the initiation and progression of disease by maintaining the production of new tumor cells. Our preliminary data demonstrate that MM stem cells resemble B cells rather than plasma cells and have the capacity to self-renew and produce progeny that subsequently differentiate into mature non-dividing plasma cells. A better understanding of the biology of MM stem cells is critical as therapies that inhibit their self-renewal may limit the production of new tumor cells. Conversely, treatments that affect mature plasma cells may induce clinical remissions, but cannot be potentially curative unless they also impact upon malignant progenitors. We hypothesize that the study of MM stem cells through a combination of clinical trials and correlative laboratory studies will provide continuous insight into the biology of MM and form the basis for novel therapies in MM. Accordingly, the specific aims of this proposal are to: (1) isolate and study the biology of MM stem cells; (2) develop further clinical strategies to target MM stem cells; and (3) Determine the effects of clinically targeting MM stem cells using monoclonal antibodies against antigens expressed on MM stem cells. Both clinical outcomes and laboratory correlates will be integrated to serve as the foundation for the development of subsequent generations of clinical trials.